The purpose of this project is to determine the role of glucagon in health and its contribution to the endogenous hyperglycemia of diabetes mellitus. The role of glucagon in health would be determined in normal humans and by dogs by somatostatin-induced suppression of glucagon during conditions of glucose need, e.g. stress, starvation and exercise. The importance of glucagon in the diabetic state would be tested by sudden insulin withdrawal in totally depancreatized humans, by studying the effect of exogenous glucagon administered to adult type and juvenile diabetics, and by studying glucagon's relationship to glycemia in the insulin-independent Houssay dog. The mechanism of the insulin-independent evanescence of glucagon's action on the liver would be studied to determine whether this "fade", demonstrated thus far only during constant rate infusions of exogenous glucagon, represents "down-regulation" of glucagon receptors and, if so, if it occurs with the phasic hyperglucagonemia of endogenous glucagon release in diabetes. The nature of the A-cell dysfunction in human diabetes would be studied to determine whether or not insulin can correct the defects or whether there is a lesion unresponsive to normal levels of plasma insulin that requires an alternative means of glucagon suppression. The role of "big plasma glucagon" (BPG), a 180,000 dalton IRG with apparent glucagon-like biologic activity and a familial distribution, would be characterized and its tissue of origin searched for. The role of the D-cells in health and in diabetes would be studied in isolated perfused dog pancreas preparations and an attempt to characterize their function in the normal and diabetic pancreas. Finally, to determine if agents which reduce the abnormal secretory patterns of glucagon that characterize human diabetes provide a useful adjunct to conventional therapeutic methods, trials of glucagon-suppressing analogues of somatostatin would be conducted.